The tumor suppression activity of the retinoblastoma protein (pRb) is well established, as mutations in the retinoblastoma gene are associated with a wide variety of cancers. Tumor suppression by pRb is partly dependent on its role in differentiation, which is largely uncharacterized. Recently, the Ewen laboratory has shown that the Rb gene acts upstream of the N-ras proto-oncogene to regulate differentiation in mice. Furthermore, mice that are heterozygous for both Rb and N-ras develop thyroid adenomas that frequently metastasize. This proposal will study the genetic interaction between Rb and N-ras in parafollicular cells (C cells) of mice by measuring their metastatic potential as phenotype. The pathway by which N-ras loss contributes to metastasis is unknown, but it is thought that the migration of C-cell metastases may arise from aberrant expression of developmental Hox genes that cause C-cell migration in normal embryonic development. To understand the role of pRb and N-ras in metastasis, the effect of N-ras dosage on hox gene expression in pRb nullizygous metastases will be determined. Making the link between metastasis and embryonic development would be a valuable step in understanding malignant cancers. [unreadable] [unreadable]